The host response to antigenic challenge requires initiation, effector, and resolution phases of inflammation.[unreadable] Just as positive signals are required to initiate immune responses, the resolution of inflammation is also an[unreadable] active process that depends upon signaling through inhibitory receptors. These signals are provided to T[unreadable] cells by activating or inhibitory members of the B7:CD28 receptor family. Atopic asthma is a T cell mediated[unreadable] immune response characterized by T helper 2 type inflammation in the airway. Using a murine model of this[unreadable] disease we have shown that costimulation through CD28 is important in the initiation and maintenance of[unreadable] inflammation. We now find that inhibitory receptor function is equally critical in the regulation of airway[unreadable] inflammation. We demonstrate that there is temporally regulated induction of both PD-1 and BTLA and their[unreadable] ligands in lung cells following allergen challenge. Furthermore, mice deficient in these receptors demonstrate[unreadable] prolonged airway inflammation following a single allergen challenge. Therefore, we hypothesize that the[unreadable] regulated expression of BTLA and PD-1 on lymphocytes and their ligands HVEM, PDL1 and/or PDL2[unreadable] parenchyma! or infiltrating immune cells limit the development of chronic airway inflammation. In[unreadable] Specific Aim 1 we will focus on the regulation of ligand expression. We will determine specifically which cell[unreadable] types in the lung express each ligand and what factors regulate their expression. Using an inducible[unreadable] transgenic mouse system we will determine if overexpression of the ligand in vivo can either prevent the[unreadable] onset of lung inflammation, or terminate an ongoing inflammatory response. In addition, we will use primary[unreadable] cultured murine tracheal epithelial cells to dissect the elements that regulate expression in airway cells. In[unreadable] Specific Aim 2 we turn our focus to the T cell. Our preliminary data establishes that in the absence of PD-1[unreadable] or BTLA there is prolonged inflammation following a single allergen challenge. We will extend this[unreadable] observation to determine the role of these receptors in models of chronic allergen exposure. Furthermore,[unreadable] we will determine the contributions of cell recruitment, proliferation and or survival in the accumulation of[unreadable] lymphocytes in the lung. While aims 1 and 2 we use an experimental murine model, in aim 3 we will begin[unreadable] an analysis of these receptorligand interactions in humans. We will compare the expression and function of[unreadable] both PD-1 and BTLA in normal and asthmatic subjects. Within the context of this collaborative program we[unreadable] will interact extensively with Project 1 in our studies of epithelial cells. In project 2, the focus is on regulatory[unreadable] T cells, which may utilize inhibitory receptors such as PD-1 and BTLA to regulate T cell function. Thus, the[unreadable] synergistic interactions of the group will undoubtedly strengthen the overall group. We believe the[unreadable] combination of expertise and reagents available in this program leave us uniquely poised to delineate how[unreadable] PD-1 and BTLA limit lung inflammation. Studies such as these may provide the basis for the development of[unreadable] novel immunotherapeutic approaches to chronic inflammatory lung diseases such as asthma.